title: Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice.
abstract: Epigenetic mechanisms such as chromatin histone H3 lysine methylation and acetylation have been implicated in diabetic vascular complications. However, histone modification profiles at pathologic genes associated with diabetic nephropathy in vivo and their regulation by the angiotensin II type 1 receptor (AT1R) are not clear. Here we tested whether treatment of type 2 diabetic db/db mice with the AT1R blocker losartan not only ameliorates diabetic nephropathy, but also reverses epigenetic changes. As expected, the db/db mice had increased blood pressure, mesangial hypertrophy, proteinuria, and glomerular expression of RAGE and PAI-1 vs. control db/+ mice. This was associated with increased RNA polymerase II recruitment and permissive histone marks as well as decreased repressive histone marks at these genes, and altered expression of relevant histone modification enzymes. Increased MCP-1 mRNA levels were not associated with such epigenetic changes, suggesting post-transcriptional regulation. Losartan attenuated key parameters of diabetic nephropathy and gene expression, and reversed some but not all the epigenetic changes in db/db mice. Losartan also attenuated increased H3K9/14Ac at RAGE, PAI-1, and MCP-1 promoters in mesangial cells cultured under diabetic conditions. Our results provide novel information about the chromatin state at key pathologic genes in vivo in diabetic nephropathy mediated in part by AT1R. Thus, combination therapies targeting epigenetic regulators and AT1R could be evaluated for more effective treatment of diabetic nephropathy.
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Marpadga A
authors.initials: MA
authors.lastname: Reddy
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Putta
authors.initials: P
authors.lastname: Sumanth
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medicine, UW Medicine Lake Union, University of Washington, Seattle, Washington, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mar
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.affiliation: Department of Medicine, UW Medicine Lake Union, University of Washington, Seattle, Washington, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
authors.affiliation: Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016326:Extracellular Matrix Proteins; D006657:Histones; D018836:Inflammation Mediators; D009707:Nucleosomes; D017395:Plasminogen Activator Inhibitor 1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012319:RNA Polymerase II; D019808:Losartan